Trans -selective γ -arylation of macrocyclic N -picolinoylcycloalkylamines through palladium-catalyzed methylene sp 3 carbon–hydrogen bond activation

Bidentate Directing Groups: An Efficient Tool in C–H Bond Functionalization Chemistry for the Expedient Construction of C–C Bonds

“…Since the first use of a picolinamide derivative as a bidentate directing group in 2005 by Daugulis, a variety of functionalization reactions using this directing group have been reported. In terms of C–C bond formation, arylation, ,,− alkylation, ,− alkenylation, ,− alkynylation, ,, oxidative annulation, , carbonylation, carboxyarylation, cyanation, − and trifluoromethylation, reactions have all been reported with the aid of a picolinamide moiety. This auxiliary has been used for the functionalization of amine derivatives because functionalized amine derivatives generate the desired product after removal of the picolinamide auxiliary.…”

“…348 The authors designed a new picolinamide directing group by introducing a silyl protected methylene hydroxyl group at the ortho-position of picolinamide (as shown in 39 and 40), which could then be used to facilitate amide cleavage through an intramolecular acyl transfer under mildly acidic conditions to form the functionalized amine 41 and the auxiliary precursor 42 (Scheme 71). 348 Because of the importance of C(sp 3 )−H functionalization, arylation reactions involving various other aliphatic amine derivatives, such as, the C(sp 3 )−H arylation of cyclopropyl methylamine (Scheme 70c), 353 the δ-C(sp 3 )−H arylation of pinanamine derivatives (Scheme 70d), 339 the γ-C(sp 3 )−H arylation of cycloalkylamines (Scheme 70e), 355 the β-C(sp 3 )− H arylation of amides (Scheme 70f), 359 the C(sp 3 )−H diarylation of rimantadine derivatives (Scheme 70g), 342 the C(sp 3 )−H arylation of 3-aminopiperidine derivatives (Scheme 70h), 345 the γ-C(sp 3 )−H arylation of macrocyclic amines (Scheme 70i), 354 the γ-C(sp 3 )−H monoarylation of amino acid derivatives (Scheme 70j), 341 the unsymmetrical diarylation of amino acid derivatives (Scheme 70k), 341 C(sp 3 )−H arylation of saturated bicyclic amine scaffolds (Scheme 70l), 338 and the γ-C(sp 3 )−H arylation of quinuclidine derivatives (Scheme 70m) 343 have been reported. All of the above arylation reactions involved the use of aryl halides and a Pd-catalyst with the aid of a picolinamide as an efficient bidentate directing group.…”

Pd-Mediated γ-C(sp3)–H Bond Activation in Ammonia–Ugi 4-CR Adducts by Using Picolinamide as Directing Group

“…This technological advance in the activation subsequently led Chen and co-workers to develop a practical regio- and stereoselective strategy of arylation and alkenylation of γ-C­(sp 3 )–H bonds in cyclohexanes mediated by 2-picolinamide (PA) and palladium acetate (Scheme , C) . Specifically, the DG picolinamide has been extensively studied for accessing C­(sp 3 /sp 2 )–C­(sp 3 /sp 2 ), C­(sp 3 /sp 2 )–O, C­(sp 3 /sp 2 )–B, C­(sp 3 )–Si, C­(sp 2 )–S, C­(sp 2 )–X (X = Br, I, Cl), and C­(sp 3 /sp 2 )–N bonds from substrates derived, for example, from (a) alkylamines and alkylamides, (b) arylamines, (c) α-amino acids, (d) peptides, (e) 3–7-membered rings, (f) macrocycles, and (g) bi- and tricyclic systems, offering a new entry to the functionalization of molecules of interest in medicinal chemistry and materials science. It is important to note that one of the unsolved challenges of these processes continues to be the lack of methodologies that allow rapid and economical access to the starting materials that possess the DG.…”